Search PubMed⌕ Search

Biomedical subjects

D M Smith

Publications and source records attributed to D M Smith.

At least 289 records · Page 16Linked to original sources
PubMed1989

Allogeneic transplantation of blood-derived, T cell-depleted hemopoietic stem cells after myeloablative treatment in a patient with acute lymphoblastic leukemia.

This report describes an allogeneic peripheral blood stem cell transplant in a patient who had received marrow ablative therapy. The patient was an 18-year-old white male with acute lymphocytic leukemia in third remission for whom an allogeneic bone marrow transplant was recommended. His HLA-identical sibling preferred to donate peripheral blood stem cells rather than marrow. The donor cells were collected with 10 apheresis procedures and depleted of T lymphocytes to prevent excessive graft-versus-host disease. Nine collections were cryopreserved. The patient received high-dose cytosine arabinoside and 12 Gy of total body irradiation, followed by infusion of all cryopreserved donor cells. A portion of the tenth apheresis product collected on the day of transplant containing 1.8 x 10(9) T lymphocytes was infused without further processing to approximate the number of T lymphocytes given in an allogeneic bone marrow transplant; the remainder was T lymphocyte depleted and infused. More than 1 x 10(9)/l granulocytes were present on day +11. A bone marrow biopsy on day +27 showed trilineage engraftment. Cytogenetic studies demonstrated that the recipient's marrow and peripheral blood were populated exclusively with donor cells. Allogeneic peripheral stem cell transplantation produced an early hematopoietic engraftment. Since the patient died on day +32, sustained engraftment could not be evaluated.

Adolescent↗
PubMed1988

Evidence that a novel serine kinase catalyses phosphorylation of the insulin receptor in an insulin-dependent and tyrosine kinase-dependent manner.

Insulin receptor was co-purified from human placenta together with insulin-stimulated kinase activity that phosphorylates the insulin receptor on serine residues. By using this 'in vitro' system, the mechanism of activation of the serine kinase by insulin was explored. Peptide 1150, histone, poly(Glu-Tyr), eliminating Mn2+ (Mg2+ only), treatment at 37 degrees C (1 h), N-ethylmaleimide, phosphate, beta-glycerol phosphate and anti-phosphotyrosine antibody all inhibited insulin-receptor tyrosine kinase activity and the ability of insulin to stimulate phosphorylation of the insulin receptor on serine. Additionally, direct stimulation of the receptor tyrosine kinase by vanadate increased serine phosphorylation of the insulin receptor. Insulin-stimulated tyrosine phosphorylation preceded insulin-stimulated serine phosphorylation of the insulin receptor. The activity of the insulin-sensitive receptor serine kinase was not augmented by cyclic AMP, cyclic GMP, Ca2+, Ca2+ + calmodulin, Ca2+ + phosphatidylserine + diolein or spermine, or inhibited appreciably by heparin. Additionally, the serine kinase phosphorylated casein or phosvitin poorly and was active with Mn2+. This indicates that it is distinct from Ca2+, Ca2+/phospholipid, Ca2+/calmodulin, cyclic AMP- and cyclic GMP-dependent protein kinases, casein kinases I and II and insulin-activated ribosomal S6 kinase. Taken together, these data indicate that a novel species of serine kinase catalyses the insulin-dependent phosphorylation of the insulin receptor and that activation of this receptor serine kinase by insulin requires an active insulin-receptor tyrosine kinase.

Catalysis↗
PubMed1988

Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences.

Human platelets, when induced to degranulate by thrombin, secrete transforming growth factor-beta (TGF-beta) in a biologically latent form. In this form, TGF-beta cannot bind to its cellular receptor, nor can it be immunoprecipitated by polyclonal antisera to TGF-beta, suggesting that the receptor-binding site and other TGF-beta epitopes may be masked. Western blot analysis of the platelet secretate indicates that the latent form of TGF-beta is a 220-235 kDa complex, in which mature TGF-beta (25 kDa) is noncovalently associated with sequences from the remainder of the precursor (74 kDa), and a third unidentified entity (approximately 135 kDa). The third component is immunologically unrelated to other growth factor binding proteins. The complex is glycosylated, and gel filtration analysis suggests it may exist in solution as higher molecular weight aggregates. Further chromatographic analysis indicates that in its latent form, the platelet TGF-beta cannot bind to alpha 2-macroglobulin (alpha 2M), but that if the platelet latent TGF-beta is activated by transient acidification, the released active TGF-beta will bind to alpha 2M. We have previously identified the latent form of TGF-beta found in serum as an alpha 2M.TGF-beta complex (O'Connor-McCourt, M. D., and Wakefield, L. M. (1987) J. Biol. Chem. 262, 14090-14099). We now propose that the latent TGF-beta secreted by platelets may be a cellular delivery complex, whereas the latent form found in serum may represent a clearance complex. Thus alpha 2M may scavenge excess TGF-beta that is released when the platelet latent form is activated, possibly by the clotting process. Finally, we have shown that the latent form of TGF-beta secreted by a variety of cell types in culture is similar, if not identical to that secreted by platelets.

Amino Acid Sequence↗
PubMed1988

Two systems in vitro that show insulin-stimulated serine kinase activity towards the insulin receptor.

Two systems in vitro are described that show insulin-stimulated phosphorylation of the insulin receptor on serine residues. In the first system, insulin receptor was purified partially from Fao rat hepatoma cells by direct solubilization of the cells in Triton X-100 and chromatography on wheat-germ-agglutinin-agarose. Phosphorylation of these preparations with [gamma-32P]ATP in the presence or absence of insulin resulted in 32P incorporation exclusively into phosphotyrosine residues. Serine kinase activity towards the insulin receptor was reconstituted by adding extracts of Fao cells. Prior exposure of the cells to insulin stimulated serine kinase activity towards the insulin receptor in extracts 7.2-fold. A receptor serine kinase activity enhanced by treatment of cells with cyclic AMP analogues was also retained in the reconstituted system. In the second system, insulin receptor and insulin-sensitive serine kinase activity towards the insulin receptor were co-purified from human placenta. The protocol involved preparation of membranes, before solubilization and chromatography on wheat-germ-agglutinin-agarose, by using gentle procedures designed not to disrupt a potentially labile association between the insulin receptor and the serine kinase. Serine kinase activity in these preparations towards the insulin receptor was stimulated up to 10-fold by insulin, and the stoicheiometry of serine phosphorylation was estimated to be approx 0.8 mol/mol of insulin receptor for phosphorylations performed in the presence of insulin. Thus a preparation of insulin receptor is described for the first time that is phosphorylated to high stoicheiometry on serine in an insulin-dependent manner. Conditions that facilitate recovery and assay of serine kinase activity are defined and discussed. These systems provide a basis for characterizing the nature of the insulin-sensitive serine kinase that phosphorylates the insulin receptor, and defining its role in insulin action and control of receptor function.

Animals↗
PubMed1988

Possible prognostic significance of human papillomavirus type in cervical cancer.

While several different human papillomaviruses (HPV) have been associated with cancer of the cervix, it is yet to be determined if specific HPV types have clinical or prognostic significance. To address this question, 30 cases of invasive carcinoma (squamous carcinoma, adenosquamous carcinoma, and adenocarcinoma) with HPV DNA sequences detectable in the tissue were analyzed. HPV type was determined by Southern blot DNA hybridization. Clinical information was obtained by chart review, and all biopsy and surgical specimens were reviewed microscopically without knowledge of HPV type. HPV 16 was detected in 14 cases, HPV 18 in 6, and HPV 31 in 2. In eight samples there were distinctly different, but as yet uncharacterized, HPV DNAs. Of the factors evaluated, tumor grade was found to have a statistically significant relationship to HPV type. Eighty-three percent of HPV 18-associated tumors were grade 3 tumors (5 of 6) as compared to only 7% of HPV 16-associated tumors (1 of 14) (P = 0.002). Age at diagnosis and nodal status in relation to HPV type exhibited a trend but were not statistically significant. The mean age of the HPV 18 group was 37 years, compared to 49 years for the HPV 16 group. Similarly, among Stage IB cancers, nodal involvement was associated with 60% of HPV 18 cases (3 of 5) as compared with 36% of HPV 16 cases (4 of 11). These observations suggest that HPV 18 may be associated with a more aggressive form of cervical cancer than other HPV types.

Adenocarcinoma↗
PubMed1988

Acute myelogenous leukemia with eosinophilic differentiation and trisomy-1.

A 50-year-old woman presented with anemia and eosinophilia. Her bone marrow biopsy, peripheral blood, and clinical features were consistent with a diagnosis of an evolving acute myelogenous leukemia. Striking dysplastic eosinophilic differentiation associated with trisomy-1 was evident, and eosinophil granule major basic protein was detected in involved tissue. Trisomy-1 has not been previously reported in association with acute myelogenous leukemia showing eosinophilic differentiation. Intensive cytotoxic chemotherapy produced a short-lived clinical and cytogenetic remission. At autopsy multiple tumor nodules composed of dysplastic eosinophil precursors and myeloblasts were evident in multiple organs.

Bone Marrow↗
PubMed1988

Postdischarge care and readmissions.

A multifaceted intervention was hypothesized to increase postdischarge ambulatory contacts and to reduce nonelective readmissions. Patients (N = 1,001) discharged from the general medicine service were stratified by risk for nonelective readmission and randomized to the control or intervention group. Intervention patients received phone calls from nurses, mailings of appointment reminders and lists of early warning signs, and prompt rescheduling of visit failures. Patients were followed for 6 months, and the results were computed in units per patient per month. The intervention group had 10.4% more total office contacts (0.53 vs 0.48, P = 0.005) than the control group. Although the intervention group had 7.6% fewer nonelective readmission days (0.85 vs 0.92), this was not statistically significant (P = 0.5). Patients in the intervention group at high risk (N = 181) had 28.1% more office visits (0.73 vs 0.57, P less than 0.01) and 31.9% fewer nonelective readmission days (1.13 vs 1.66), but this was also not statistically significant (P = 0.06). Thus, the intervention significantly increased post-discharge contacts, primarily in high-risk patients, but failed to reduce the incidence of nonelective readmission days significantly.

Aftercare↗
PubMed1988

The cost-effectiveness of intensive postdischarge care. A randomized trial.

This study tested the hypothesis that increasing the intensity of outpatient care for patients discharged from the hospital could lower their subsequent inpatient and total health-care costs. At discharge, 1,001 patients were stratified by risk of readmission (low, medium, or high) and randomly assigned to the intervention or control group. Discharge information (summaries, medications, and postdischarge needs) was provided to outpatient nurses who monitored intervention patients closely and attempted to resolve their problems. Intervention patients also received appointment reminders, and missed visits were promptly rescheduled. The cost of the intervention was $5.20 per patient per month. High-risk patients in the intervention group had significantly higher outpatient costs ($131/month vs. $107/month; P = 0.02), but lower inpatient costs ($535/month vs. $800/month; P = 0.02) than high-risk patients in the control group. Reduced inpatient costs in the high-risk intervention group were attributed to shorter, less intensive hospital stays. In conclusion, increasing ambulatory care resources after hospital discharge for high-risk patients may reduce health-care costs associated with readmission to the hospital.

Aftercare↗
PubMed1988

Cellular pathways for rejection of class-I-MHC--disparate skin and tumor allografts.

We have investigated the relative roles of the Lyt-2+ and L3T4+ T lymphocyte subsets in rejection of class-I-MHC-antigen-disparate skin and tumor allografts. To deplete T cells in vivo, rat anti-Lyt-2 or anti-L3T4 monoclonal antibodies (mAb) were administered to adult-thymectomized (ATX) recipient mice prior to transplantation. BALB/c (H-2d) recipient mice rejected the Ia- Sarcoma I (Sa1) (H-2a) tissue culture-derived tumor after depletion of the L3T4+ T cell subset in vivo. In contrast, depletion of the Lyt-2+ T cell subset permitted lethal tumor growth in all recipient mice. To determine the role of particular T cell subsets in rejection of Ld class-I-MHC-antigen-disparate allografts, BALB/c skin was transplanted to BALB/c-H-2dm2 recipient mice. Skin grafts were rejected by control mice with a mean survival time (MST) of 14.5 days. The MST of skin grafts for mice treated with anti-L3T4 mAb was 16.6 days. In contrast, administration of anti-Lyt-2 mAb alone (MST = greater than 47 days) or together with anti-L3T4 mAb (MST = greater than 50 days) caused prolonged or indefinite graft survival in all recipient mice. Depletion of specific T cell subsets was confirmed by flow cytometric analysis and by analysis of T cell function in vitro. These results suggest that Lyt-2+ T lymphocytes are essential for rejection of class-I-MHC-disparate allografts; indirect presentation of alloantigen to L3T4+ T cells may not be necessary for rejection.

Animals↗
PubMed1988

Eminence development of the postnatal human temporomandibular joint.

The objective of this study was to analyze postnatal eminence development quantitatively, as a first step in defining the relationship between loading of the TMJ and eminence development. A sample of human osteological remains provided the temporal bones of forty-nine (49) individuals of ages between birth and twenty years. An angular measurement technique permitted quantification of the degree of eminence development of each individual. It was concluded that: (i) the TMJ eminence reaches more than 50% of mature size, and exhibits mature morphology, by the time of completion of eruption of the primary dentition; (ii) the maximum velocity of development of the eminence takes place before three years of age; and (iii) the velocity of development of the eminence is reduced at about five years of age, and slowly diminishes to zero by the middle to late teens.

Adolescent↗
PubMed1988

A theoretical model of loading and eminence development of the postnatal human temporomandibular joint.

The objectives of the present study were to characterize the loading of the immature TMJ, and to develop a theoretical model to explain the relationship between joint loading and development of the eminence of the human TMJ. The osteological remains of forty individuals, ages ranging from birth to twenty years, were used to provide metric coordinates of the three-dimensional relationships of the anatomy of the biting apparatus. The data were used, in a numerical model of TMJ loading (Smith et al., 1986), to calculate the magnitudes and directions of condylar loading. The following conclusions were drawn: (i) static equilibrium cannot be satisfied unless the immature TMJ is loaded; (ii) in the neonate, the direction of condylar loading is approximately vertical but, as the child matures, the angle of condylar loading becomes more oblique; and (iii) evidence is given in support of the hypothesis that early development of the eminence is consequent upon the stimulation of bone growth by the appropriate position and timing of loading of the immature condyle on the temporal component of the joint.

Adolescent↗
PubMed1988

A mortality study of vinyl chloride monomer workers employed in the United Kingdom in 1940-1974.

The mortality experience of 5,498 male workers employed for at least one year during 1940-1974 in the vinyl chloride industry of the United Kingdom was followed through to 31 December 1984. There was a significant excess of nonsecondary liver tumors with 11 deaths, of which seven were angiosarcomas. All the angiosarcoma deaths occurred in autoclave workers with a median latency of 25 years from date of first exposure. A strong healthy worker effect was seen. Other than that for liver cancer, no increased incidence of cancer deaths attributable to vinyl chloride monomer exposure was found. There was no evidence of increased mortality from chronic liver disease. The incidence of death from respiratory disease was low and was not affected by polyvinyl chloride dust exposure.

Adult↗
PubMed1988

Mesothelioma in Great Britain in 1968-1983.

The British mesothelioma register records deaths in Great Britain when the word "mesothelioma" is on the death certificate. In 1968-1983 the mesothelioma deaths among men increased from 114 to 467, while those among women increased from 38 to 90. In 1983 the crude mesothelioma death rates were 17.5 per million and 3.2 per million for the men and women, respectively. The Northern region had the highest crude rates. At the county level, the highest crude deaths rates in 1976-1983 were recorded for the men in Devon and for the women in Lancashire. Marked differences occurred in the ratio of deaths among men to deaths among women for mesothelioma of the pleura (4.6:1) and for mesothelioma of the peritoneum (2:1). The age-specific death rates for men and women diverged markedly for pleural mesothelioma but not for peritoneal mesothelioma. Trends in the use of asbestos and in age- and sex-specific death rates suggest that the annual number of mesothelioma deaths will continue to increase, possibly until the turn of the century. This increase will be concentrated among the men as the main asbestos exposure of women occurred during the war and the annual deaths due to this exposure may have already peaked.

Adult↗
PubMed1988

Autologous peripheral hematopoietic stem cell transplantation restores hematopoietic function following marrow ablative therapy.

From ten patients with advanced malignant disease involving the bone marrow, autologous hematopoietic stem cells were collected from the peripheral blood during eight four-hour pheresis procedures and cryopreserved. No manipulations to increase the number of stem cells circulating in the blood were used during the collections. Following marrow ablative chemotherapy or chemoradiotherapy, the autologous cells were thawed and infused intravenously (IV). WBCs reappeared in the circulation at a median of eight days (range seven to 11 days) after stem cell infusion. Two patients died early, whereas the other eight reached normal numbers of circulating granulocytes that have persisted for up to greater than 20 months. These eight patients became independent of RBC transfusions (hemoglobin concentration greater than 10 g/dL) at a median of 27 days (range 11 to 58 days) after transplantation. One patient received platelet transfusions for counts less than 50 x 109)/L, one patient developed a clinical picture of idiopathic thrombocytopenic purpura, and six patients maintained a platelet count greater than 20 x 10(9)/L at a median of 23 days (range 14 to 25 days) following stem cell infusion. This technique allows patients ineligible for autologous bone marrow transplantation due to unacceptable anesthetic risks, prior pelvic irradiation, or bone marrow metastases to receive marrow ablative therapy.

Bone Marrow↗
PubMed1988

The fibrogenic response of adult rat lung to continuous propranolol treatment.

Fibrogenesis is a common pulmonary response to injury, which is usually preceded by other severe reactions, including inflammation, fluid exudation, and alveolar epithelial damage and proliferation. The purpose of this study was to examine the morphologic effects on the distal lung of a continuous propranolol treatment. Adult male rats were treated, via a subcutaneous osmotic pump, with a continuous (approximately 0.5 mg/hour) dose of propranolol HCl, a potent wide range beta-adrenergic blocking agent, in saline, or saline alone. The animals were killed after one week or three weeks. Electron microscopy of the lungs of the propranolol-treated animals revealed a dramatic increase in the prominence of interstitial cells and fibers of the alveolar septa, along with focal thickening of endothelial cells and some morphologic changes in type II alveolar epithelial cells. In some animals an analysis of total protein content, as well as 3H-proline incorporation into total protein and collagen was undertaken. The results of this study indicated a significant increase in total protein content and proline incorporation into collagen in the lungs of animals treated for seven days with continuous propranolol. There was no evidence of stimulated blood cells, macrophages, edema or severe epithelial damage. This study provides morphologic evidence that continuous treatment with moderate levels of propranolol results in a fibrogenic response in the peripheral lung, in the absence of typical hallmarks of severe pulmonary damage.

Animals↗